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Differential KATP channel pharmacology in intact mouse heart

  • Alexey V. Glukhov
    Affiliations
    Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA
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  • Author Footnotes
    1 Present and permanent address: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., C-2114, Bethesda, MD 20814, USA.
    Thomas P. Flagg
    Footnotes
    1 Present and permanent address: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., C-2114, Bethesda, MD 20814, USA.
    Affiliations
    Department of Cell Biology and Physiology, Box 8228, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
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  • Vadim V. Fedorov
    Affiliations
    Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA
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  • Igor R. Efimov
    Affiliations
    Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA
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  • Colin G. Nichols
    Correspondence
    Corresponding author. Tel.: +1 314 362 6630; fax: +1 314 362 7463.
    Affiliations
    Department of Cell Biology and Physiology, Box 8228, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
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  • Author Footnotes
    1 Present and permanent address: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., C-2114, Bethesda, MD 20814, USA.
Published:September 09, 2009DOI:https://doi.org/10.1016/j.yjmcc.2009.08.026

      Abstract

      Classically, cardiac sarcolemmal KATP channels have been thought to be composed of Kir6.2 (KCNJ11) and SUR2A (ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have assessed the effects of isotype-specific potassium channel-opening drugs, diazoxide (specific to SUR1>SUR2A) and pinacidil (SUR2A>SUR1), in intact hearts from wild-type mice (WT, n=6), SUR1−/− (n=6), and Kir6.2−/− mice (n=5). Action potential durations (APDs) in both atria and ventricles were estimated by optical mapping of the posterior surface of Langendorff-perfused hearts. To confirm the atrial effect of both openers, isolated atrial preparations were mapped in both WT (n=4) and SUR1−/− (n=3) mice. The glass microelectrode technique was also used to validate optical action potentials. In WT hearts, diazoxide (300 μM) decreased APD in atria (from 33.8±1.9 ms to 24.2±1.1 ms, p<0.001) but was without effect in ventricles (APD 60.0±7.6 ms vs. 60.8±7.5 ms, respectively, NS), consistent with an atrial-specific role for SUR1. The absence of SUR1 resulted in loss of efficacy of diazoxide in SUR1−/− atria (APD 36.8±1.9 ms vs. 36.8±2.8 ms, respectively, NS). In contrast, pinacidil (300 μM) significantly decreased ventricular APD in both WT and SUR1−/− hearts (from 60.0±7.6 ms to 29.8±3.5 ms in WT, p<0.001, and from 63.5±2.1 ms to 24.8±3.8 ms in SUR1−/−, p<0.001), but did not decrease atrial APD in either WT or SUR1−/− hearts. Glibenclamide (10 μM) reversed the effect of pinacidil in ventricles and restored APD to control values. The absence of Kir6.2 subunits in Kir6.2−/− hearts resulted in loss of efficacy of both openers (APD 47.2±2.2 ms vs. 47.6±2.1 ms and 50.8±2.4 ms, and 90.6±5.7 ms vs. 93.2±6.5 ms and 117.3±6.4 ms, for atria and ventricle in control versus diazoxide and pinacidil, respectively). Collectively, these results indicate that in the same mouse heart, significant differential KATP pharmacology in atria and ventricles, resulting from SUR1 predominance in forming the atrial channel, leads to differential effects of potassium channel openers on APD in the two chambers.

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      References

        • Kane G.C.
        • Liu X.K.
        • Yamada S.
        • Olson T.M.
        • Terzic A.
        Cardiac KATP channels in health and disease.
        J. Mol. Cell. Cardiol. 2005 Jun; 38: 937-943
        • Nichols C.G.
        • Lederer W.J.
        Adenosine triphosphate-sensitive potassium channels in the cardiovascular system.
        Am. J. Physiol. 1991; 261: H1675-H1686
        • Billman G.E.
        The cardiac sarcolemmal ATP-sensitive potassium channel as a novel target for anti-arrhythmic therapy.
        Pharmacol. Ther. 2008; 120: 54-70
        • Flagg T.P.
        • Patton B.
        • Masia R.
        • Mansfield C.
        • Lopatin A.N.
        • Yamada K.A.
        • et al.
        Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[DeltaN30,K185Q] in the heart.
        Am. J. Physiol. Heart Circ. Physiol. 2007 Jul; 293: H836-H845
        • Suzuki M.
        • Li R.A.
        • Miki T.
        • Uemura H.
        • Sakamoto N.
        • Ohmoto-Sekine Y.
        • et al.
        Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice.
        Circ. Res. 2001; 88: 570-577
        • Gumina R.J.
        • Pucar D.
        • Bast P.
        • Hodgson D.M.
        • Kurtz C.E.
        • Dzeja P.P.
        • et al.
        Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics.
        Am. J. Physiol. Heart Circ. Physiol. 2003; 284: 2106-2113
        • Kane G.C.
        • Behfar A.
        • Dyer R.B.
        • O'Cochlain D.F.
        • Liu X.K.
        • Hodgson D.M.
        • et al.
        KCNJ11 gene knockout of the Kir6.2 KATP channel causes maladaptive remodeling and heart failure in hypertension.
        Hum. Mol. Genet. 2006 Aug 1; 15: 2285-2297
        • Yamada S.
        • Kane G.C.
        • Behfar A.
        • Liu X.K.
        • Dyer R.B.
        • Faustino R.S.
        • et al.
        Protection conferred by myocardial ATP-sensitive K+ channels in pressure overload-induced congestive heart failure revealed in KCNJ11 Kir6.2-null mutant.
        J. Physiol. 2006 December; 577: 1053-1065
        • Babenko A.P.
        • Gonzalez G.
        • Aguilar-Bryan L.
        • Bryan J.
        Reconstituted human cardiac KATP channels: functional identity with the native channels from the sarcolemma of human ventricular cells.
        Circ. Res. 1998; 83: 1132-1143
        • Inagaki N.
        • Gonoi T.
        • Clement J.P.
        • Wang C.Z.
        • Aguilar-Bryan L.
        • Bryan J.
        • et al.
        A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels.
        Neuron. 1996; 16: 1011-1017
        • Shi N.Q.
        • Ye B.
        • Makielski J.C.
        Function and distribution of the SUR isoforms and splice variants.
        J. Mol. Cell. Cardiol. 2005; 39: 51-60
        • Dhar-Chowdhury P.
        • Harrell M.D.
        • Han S.Y.
        • Jankowska D.
        • Parachuru L.
        • Morrissey A.
        • et al.
        The glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase, triose-phosphate isomerase, and pyruvate kinase are components of the K(ATP) channel macromolecular complex and regulate its function.
        J. Biol. Chem. 2005 Nov 18; 280: 38464-38470
        • Crawford R.M.
        • Budas G.R.
        • Jovanovic S.
        • Ranki H.J.
        • Wilson T.J.
        • Davies A.M.
        • et al.
        M-LDH serves as a sarcolemmal K(ATP) channel subunit essential for cell protection against ischemia.
        EMBO J. 2002 Aug 1; 21: 3936-3948
        • Crawford R.M.
        • Ranki H.J.
        • Botting C.H.
        • Budas G.R.
        • Jovanovic A.
        Creatine kinase is physically associated with the cardiac ATP-sensitive K+ channel in vivo.
        FASEB J. 2002 Jan; 16: 102-104
        • Jovanovic S.
        • Du Q.
        • Crawford R.M.
        • Budas G.R.
        • Stagljar I.
        • Jovanovic A.
        Glyceraldehyde 3-phosphate dehydrogenase serves as an accessory protein of the cardiac sarcolemmal K(ATP) channel.
        EMBO Rep. 2005 Sep; 6: 848-852
        • Elrod J.W.
        • Harrell M.
        • Flagg T.P.
        • Gundewar S.
        • Magnuson M.A.
        • Nichols C.G.
        • et al.
        Role of sulfonylurea receptor type 1 subunits of ATP-sensitive potassium channels in myocardial ischemia/reperfusion injury.
        Circulation. 2008 Mar 18; 117: 1405-1413
        • Morrissey A.
        • Rosner E.
        • Lanning J.
        • Parachuru L.
        • Dhar Chowdhury P.
        • Han S.
        • et al.
        Immunolocalization of KATP channel subunits in mouse and rat cardiac myocytes and the coronary vasculature.
        BMC Physiol. 2005; 5: 1
        • Flagg T.P.
        • Kurata H.T.
        • Masia R.
        • Caputa G.
        • Magnuson M.A.
        • Lefer D.J.
        • et al.
        Differential structure of atrial and ventricular KATP: atrial KATP channels require SUR1.
        Circ. Res. 2008 Dec 5; 103: 1458-1465
        • Liu Y.
        • Ren G.
        • O'Rourke B.
        • Marban E.
        • Seharaseyon J.
        Pharmacological comparison of native mitochondrial KATP channels with molecularly defined surface KATP channels.
        Mol. Pharmacol. 2001 February 1; 59: 225-230
        • Shiota C.
        • Larsson O.
        • Shelton K.D.
        • Shiota M.
        • Efanov A.M.
        • Hoy M.
        • et al.
        Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose.
        J. Biol. Chem. 2002 Oct 4; 277: 37176-37183
        • Miki T.
        • Nagashima K.
        • Tashiro F.
        • Kotake K.
        • Yoshitomi H.
        • Tamamoto A.
        • et al.
        Defective insulin secretion and enhanced insulin action in KATP channel- deficient mice.
        Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10402-10406
      1. Glukhov AV, Fedorov VV, Mohler PJ, Anderson ME, Efimov IR. Functional anatomy of the murine sinus node: evidence from high-resolution optical mapping. AJP. 2009(Submitted).

        • Fedorov V.V.
        • Lozinsky I.T.
        • Sosunov E.A.
        • Anyukhovsky E.P.
        • Rosen M.R.
        • Balke C.W.
        • et al.
        Application of blebbistatin as an excitation–contraction uncoupler for electrophysiologic study of rat and rabbit hearts.
        Heart Rhythm. 2007 May; 4: 619-626
        • Fedorov V.V.
        • Kostecki G.
        • Hemphill M.
        • Efimov I.R.
        Atria are more susceptible to electroporation than ventricles: implications for atrial stunning, shock-induced arrhythmia and defibrillation failure.
        Heart Rhythm. 2008 Apr; 5: 593-604
        • Fedorov V.V.
        • Li L.
        • Glukhov A.
        • Shishkina I.
        • Aliev R.R.
        • Mikheeva T.
        • et al.
        Hibernator Citellus undulatus maintains safe cardiac conduction and is protected against tachyarrhythmias during extreme hypothermia: possible role of Cx43 and Cx45 up-regulation.
        Heart Rhythm. 2005 Sep; 2: 966-975
        • Waldeyer C.
        • Fabritz L.
        • Fortmueller L.
        • Gerss J.
        • Damke D.
        • Blana A.
        • et al.
        Regional, age-dependent, and genotype-dependent differences in ventricular action potential duration and activation time in 410 Langendorff-perfused mouse hearts.
        Basic Res. Cardiol. 2009 Mar 14;
        • Honore E.
        • Lazdunski M.
        Two different types of channels are targets for potassium channel openers in Xenopus oocytes.
        FEBS Lett. 1991; 287: 75-79
        • Baron A.
        • van B.L.
        • Monnier D.
        • Roatti A.
        • Baertschi A.J.
        A novel K(ATP) current in cultured neonatal rat atrial appendage cardiomyocytes.
        Circ. Res. 1999; 85: 707-715
        • Philip-Couderc P.
        • Tavares N.I.
        • Roatti A.
        • Lerch R.
        • Montessuit C.
        • Baertschi A.J.
        Forkhead transcription factors coordinate expression of myocardial KATP channel subunits and energy metabolism.
        Circ. Res. 2008 February 1; 102: e20-35
        • Poitry S.
        • van Bever L.
        • Coppex F.
        • Roatti A.
        • Baertschi A.J.
        Differential sensitivity of atrial and ventricular K(ATP) channels to metabolic inhibition.
        Cardiovasc. Res. 2003 Feb; 57: 468-476
        • Babenko A.P.
        • Gonzalez G.
        • Bryan J.
        Pharmaco-topology of sulfonylurea receptors. Separate domains of the regulatory subunits of K(ATP) channel isoforms are required for selective interaction with K(+) channel openers.
        J. Biol. Chem. 2000; 275: 717-720
        • Ogbaghebriel A.
        • Shrier A.
        Differential responsiveness of atrial and ventricular myocytes to potassium channel openers.
        J. Cardiovasc. Pharmacol. 1995 Jan; 25: 65-74
        • Mull K.P.
        • Debnam Q.
        • Kabir S.M.
        • Bhattacharyya M.L.
        Role of action potential shortening in the prevention of arrhythmias in canine cardiac tissue.
        Clin. Exp. Pharmacol. Physiol. 1999 Dec; 26: 964-969
        • Fedorov V.V.
        • Glukhov A.V.
        • Chang R.
        • Kostecki G.
        • Schuessler R.B.
        • Nichols C.G.
        • et al.
        KATP channel openers diazoxide and pinacidil induce reentrant arrhythmias in both atria and ventricles of myopathic human hearts.
        Heart Rhythm. 2009; 6: S-359
        • Fukuzaki K.
        • Sato T.
        • Miki T.
        • Seino S.
        • Nakaya H.
        Role of sarcolemmal ATP-sensitive K+ channels in the regulation of sinoatrial node automaticity: an evaluation using Kir6.2-deficient mice.
        J. Physiol. 2008 June; 586: 2767-2778
        • Han X.
        • Light P.E.
        • Giles W.R.
        • French R.J.
        Identification and properties of an ATP-sensitive K+ current in rabbit sino-atrial node pacemaker cells.
        J. Physiol. 1996 Jan 15; 490: 337-350
        • Ogbaghebriel A.
        • Shrier A.
        Inhibition of metabolism abolishes transient outward current in rabbit atrial myocytes.
        Am. J. Physiol. 1994 Jan; 266: H182-H190
        • Faivre J.F.
        • Findlay I.
        Effects of tolbutamide, glibenclamide and diazoxide upon action potentials recorded from rat ventricular muscle.
        Biochim. Biophys. Acta. 1989; 984: 1-5
        • Flagg T.P.
        • Charpentier F.
        • Manning-Fox J.
        • Remedi M.S.
        • Enkvetchakul D.
        • Lopatin A.
        • et al.
        Remodeling of excitation–contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels.
        Am. J. Physiol. Heart Circ. Physiol. 2004; 286: H1361-H1369
        • Nerbonne J.M.
        • Nichols C.G.
        • Schwarz T.L.
        • Escande D.
        Genetic manipulation of cardiac K(+) channel function in mice: what have we learned, and where do we go from here?.
        Circ. Res. 2001 Nov 23; 89: 944-956
        • Nattel S.
        • Li D.
        • Yue L.
        Basic mechanisms of atrial fibrillation—very new insights into very old ideas.
        Annu. Rev. Physiol. 2000; 62: 51-77
        • Masia R.
        • Enkvetchakul D.
        • Nichols C.
        Differential nucleotide regulation of K(ATP) channels by SUR1 and SUR2A.
        J. Mol. Cell. Cardiol. 2005; 39: 491-501
        • Flagg T.P.
        • Remedi M.S.
        • Masia R.
        • McLerie M.
        • Lopatin A.
        • Nichols C.
        Transgenic overexpression of SUR1 in the heart exerts dominant negative effects on sarcolemmal K ATP.
        J. Mol. Cell. Cardiol. 2005; 39: 647-656